HUE031061T2 - Method for delivering interferon-beta - Google Patents

Method for delivering interferon-beta Download PDF

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Publication number
HUE031061T2
HUE031061T2 HUE06718129A HUE06718129A HUE031061T2 HU E031061 T2 HUE031061 T2 HU E031061T2 HU E06718129 A HUE06718129 A HU E06718129A HU E06718129 A HUE06718129 A HU E06718129A HU E031061 T2 HUE031061 T2 HU E031061T2
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solution
less
casing
metal
ppb
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Eric Anthony Faulkner
Biase Mary Diana Di
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Biogen Ma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/3129—Syringe barrels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0007—Special media to be introduced, removed or treated introduced into the body

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  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Communicable Diseases (AREA)
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  • Neurosurgery (AREA)
  • Virology (AREA)
  • Neurology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
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Description

Description
TECHNICAL FIELD OF THE INVENTION
[0001] This invention relates to storing lnterferon-ß. BACKGROUND OF THE INVENTION
[0002] Interferons are single chain polypeptides secreted by most animal cells in response to a variety of inducers, including viruses, mitogens and polynucleotides. Interferons participate in regulation of cell function, and have antiviral, antiproliferative and immu-nomodulating properties. Native human interferons are classified into three majortypes: Interferon-a(leukocyte), lnterferon-ß (fibroblast) and lnterferon-γ (immune). Native lnterferon-ß is produced primarily by diploid fibroblast cells and in lesser amounts by lymphoblastoid cells.
[0003] lnterferon-ß is a glycoprotein. Itsgenetic nucleic acid and amino acid sequences have been determined. (Houghton et. al., "The Complete Amino Acid Sequence of Human Fibroblast Interferon as Deduced Using Synthetic Oligodeoxyribonucleotide Primers of Reverse Transcriptase," Nucleic Acids Research, 8, pp. 2885-94 (1980); T. Taniguchi et al., "The Nucleotide Sequence of Human Fibroblast DNA," Gene, 10, pp. 11-15 (1980)). Recombinant lnterferon-ß has been produced and characterized.
[0004] lnterferon-ß exhibits various biological and immunological activities, such as antiviral, anti-tumor and anti-cancer. lnterferon-ß-1a is approved for sale in the U n ited States for the treatment of multiple sclerosis under the trade name of Avonex®.
SUMMARY OF THE INVENTION
[0005] In general, this disclosure relates to storing solutions of lnterferon-ß such that the concentration of an aggregating metal is less than 500 parts per billion in the stored solution. Aggregating metals include iron, copper, nickel, molybdenum and tungsten. Devices useful for storing lnterferon-ß include, but are not limited to, syringes, vials, bottles, bags and the like.
[0006] In one instance , the disclosure provides a method for storing and delivering solutions of Interferon-ß including providing a device having a housing for retaining the solution and filling the solution of Interferon-ß into the housing. After filling the solution, the housing releases a concentration of an aggregating metal into the solution of less than 500 parts per billion.
[0007] In another instance, the housing releases a total concentration of aggregating metals into the solution of less than 500 parts per billion, less than 250 parts per billion, less than about 100 parts per billion, less than about 75 parts per billion, less than about 50 parts per billion, or less than about than 25 parts per billion.
[0008] In still another instance, the disclosure features a method for storing and delivering solutions of Interfer- on-ß including providing a device having a housing for retaining the solution and filling the solution of Interferon-ß into the housing. After filling the solution, aggregation of lnterferon-ß caused by aggregating metals in the solution is less than 15% after storage, less than 10% after storage, less than 5% after storage, less than 2% after storage.
[0009] In yet another instance, the disclosure features a device for storing and delivering solutions of Interferon-ß including a housing for retaining an lnterferon-ß solution and a solution of lnterferon-ß wherein the housing releases a total concentration of aggregating metals into the solution of less than 500 parts per billion, less than 250 parts per billion, less than about 100 parts per billion, less than about 75 parts per billion, less than about 50 parts per billion, or less than about than 25 parts per billion.
[0010] In one instance, aggregation of lnterferon-ß caused by aggregating metals in the solution of Interfer-on-ß contained in the housing is less than 15% after storage, less than 10% after storage, less than 5% after storage, less than 2% after storage.
[0011] Instances of the disclosure include one or more of the following. The housing releases a concentration of an aggregating metal or total concentration of aggregating metals of less than 500 parts per billion after the solution is retained in the housing for greater than about 10 minutes, greater than about 120 minutes, greater than about 360 minutes, greater than about 480 minutes. The housing releases a concentration of an aggregating metal or total concentration of aggregating metals of less than about 500 parts per billion after the solution is retained in the housing between about 120 minutes to about 480 minutes or between about 300 minutes to about 420 minutes. The housing releases a concentration of an aggregating metal or total concentration of aggregating metals of less than about 250 parts per billion, less than about 100 parts per billion, less than about 75 parts per billion, less than about 50 parts per billion, less than about than 25 parts per billion. The aggregating metal is iron, copper, nickel, molybdenum or tungsten. The device is a syringe, bottle, vial ora bag. The housing of the device is constructed of glass, metal or plastic. The Interferon-ß is lnterferon-ß-1a.
[0012] Based on the disclosure that is contained herein, the present invention provides a method for producing a device that includes a housing for retaining a solution of lnterferon-ß, wherein the method comprises: (a) cleaning the housing with acid and basic washes so as to remove or reduce the amount of aggregating metal on the surface that, in use, would be in direct contact with the solution of lnterferon-ß; (b) filling the solution of lnterferon-ß into the housing, wherein, after filling the solution, the housing releases a concentration of aggregating metal into the solution of less than 500 parts per billion after the solution is retained in the housing forgreater than about 10 minutes.
[0013] In a related aspect, the present invention provides a method for producing a device that includes a housing for retaining a solution of lnterferon-β, wherein the method comprises: (a) constructing the housing so as to reduce the amount of aggregating metal on the surface that, in use, would be in direct contact with the solution of lnterferon-β; (b) filling the solution of Interferon-ß into the housing, wherein, afterfilling the solution, the housing releases a concentration of aggregating metal into the solution of less than 500 parts per billion after the solution is retained in the housing forgreaterthan about 10 minutes.
[0014] In a further aspect, the invention provides a device comprising: (a) a housing for retaining a solution of Interferon-ß; (b) a solution of Interferon-ß retained within the housing, wherein the housing releases a concentration of aggregating metal into the Interferon-ß solution of less than 500 parts per billion after the solution is retained in the housing for greater than about 10 minutes.
[0015] The present invention and embodiments thereof are set out in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016]
Figure 1 is a plot of the percent aggregation of Inter-feron-ß-1a as a function of time and the concentration of an aggregating metal, tungsten, after four weeks of storage in a commercially available syringe containing aggregating metals at 25°C at 60% relative humidity.
Figure 2 illustrates a device for storing Interferon-B. Figure 3 is an end-on view of the device shown in Fig. 2 taken along the segment A.
Figure 4 illustrates alternative devices useful for storing Interferon-B. DETAILED DESCRIPTION OF THE INVENTION Definitions [0017] As used herein, the term "Interferon-ß" refers to all forms of interferon-ß such as interferon-ß-1a.
[0018] As used herein, the term "aggregation" refers to increased interaction between Interferon molecules to cause increased opalescence, particulate formation or precipitation of the Interferon-ß from solution.
[0019] As used herein, the term "aggregating metals in an amount less than a certain number of parts per billion" refers to the amount of aggregating metals which are carried from the housing of a device into a wash solution of Avonex® liquid formulation, in which the wash solution is placed in contact with the device housing for about 240 minutes to about 480 minutes, for about 300 minutes to about 420 minutes, orfrom about 345 minutes to about 375 minutes.
[0020] As used herein, the term "less than a certain number of parts per billion of tungsten" refers to the amount of aggregating metals which are carried from the housing of a device into a wash solution of Avonex® liquid formulation, in which the wash solution is applied to the device housing for about 240 minutes to about 480 minutes, for about 300 minutes to about 420 minutes, orfrom about 345 minutes to about 375 minutes.
[0021] As used herein, the term "device" refers to any means for storing or delivering Interferon-B.
[0022] As used herein, the term housing" refers to an element of a device that is in direct contact with Interfer-on-ß for more than about 10 minutes.
[0023] As used herein, the term "wash solution" refers to the solution, such as a placebo formulation, used to determine the amount of an aggregating metal released from the device into the solution.
[0024] As used herein, the term "placebo formulation" refers to the solution including the components of a drug composition without the drug.
[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, the materials, methods and examples are illustrative only and not intended to be limiting.
[0026] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
Description of the Invention [0027] In general, the disclosure relates to a method for storing and delivering solutions of Interferon-ß such that the concentration of aggregating metal (each metal individually or total of all aggregating metals) is less than 500 parts per billion in the solution after storage, e.g., after storage greater than 10 minutes, 120 minutes, 360 minutes, or 480 minutes. Certain metals cause aggregation of Interferon-ß. For example, as shown in Figure 1, an increasing concentration of the aggregating metal, such as tungsten, increases the degree of aggregation of interferon-ß-1a.
[0028] Aggregation is undesirable because it causes opalescence, particulate formation and precipitation of the drug. Further, aggregation can lead to a lower bioavailability of the drug and difficulty in delivering the Interferon-ß. The method described herein reduces the amount of aggregating metals released into a stored solution of Interferon-ß to provide less than about 15%, 10%, 5%, or 2% aggregation as measured by size ex- elusion chromatography.
[0029] The invention provides a device for retaining a solution of lnterferon-ß so that the concentration of aggregating metals (each metal individually or the total of all aggregating metals) is less than 500 parts per billion in the solution after the solution is retained in the device for greater than 10 minutes, 120 minutes, 360 minutes, or 480 minutes. In addition, the device described herein, reduces the amount of aggregating metals released into an lnterferon-ß solution retained within the housing to provide less than about 15%, 10%, 5%, or 2% aggregation.
[0030] Referring to Figures 2 and 3, a glass syringe 10 for delivering lnterferon-ß includes a housing 20 for holding lnterferon-ß-1a and a needle 30 for dispensing Inter-feron-ß-1a from housing 20 (Figure 2). The housing 20 includes a cylindrical wall 22 defining a central bore 24 (Figure 3). One end 26 of the housing connects to needle 30 and the other end 28 of the housing receives a plunger 32. Plunger 32 is disposed in central bore 24 to engage frictionally cylindrical wall 22. During delivery, plunger 32 is depressed to dispense lnterferon-ß. During storage in syringe 10, an lnterferon-ß solution is disposed in central bore 24 of housing 20 and is in physical contact with the end of plunger 32.
[0031] Syringe 10 is constructed or cleaned prior to use to remove or reduce the amount of aggregating metals on the surfaces of the syringe which would contact a solution of lnterferon-ß. Generally, syringe 10 is constructed or cleaned prior to use to remove or reduce the amount of aggregating metals, such as iron, copper, nickel, molybdenum or tungsten, released from the surfaces of the syringe that would be in contact with the Interferon-ß solution during storage, e.g., greater than about 10, 120, 360, or 480 minutes, about 100, 200, 400, 700 or 1000 hours, between about 120 minutes to about 480 minutes, or between about 300 minutes to about 420 minutes of storage at temperatures between 2°C and 30°C.
[0032] Syringe 10 is constructed or cleaned such that less than 500, 250, 100, 75, 50 or 25 parts per billion of aggregating metals (individually or in total) are released from the syringe into a solution of lnterferon-ß after storage. The construction or cleaning of the syringe also provides less than 15%, 10%, 5% or 2% aggregation in an lnterferon-ß solution after storage of the solution in the syringe. The amount of aggregating metal released into a solution of lnterferon-ß or placebo formulation may be measured by performing Inductively Coupled Plasma Mass Spectrometry or Atomic Absorption Spectroscopy on lnterferon-ß solutions or placebo formulations.
[0033] Suitable syringe storage devices capable of providing storage conditions which reduce the percent aggregation and amount of aggregating metal to levels described above are available from Becton Dickinson and Bunder Glas GmbH. Other syringe storage devices are known in the art. For example, see U.S. Patent Nos. 6,352,522; 6,263,641; 4,895,716 and 4,266,557. These devices may be washed with concentrated sulfuric acid, e.g., 98%, to remove aggregating metals followed by one or more basic washes to neutralize any residual sulfuric acid before filling thedevice with lnterferon-ß. Afterwashing the device with the acid and basic solutions, the amount of aggregating metal remaining in the syringe may be determined by rinsing the syringe and performing Inductively Coupled Plasma Mass Spectrometry or Atomic Absorption Spectroscopy on a placebo formulation that was stored in the syringe for more than about 10 minutes.
[0034] Although the storage device is described above as a syringe, other devices for storing or delivering Inter-feron-ß are within the scope of the invention provided that the elements of each device that are in contact with the lnterferon-ß for more than about 10 minutes release less than 500 parts per billion of aggregating metals into the solution of lnterferon-ß. Each of these devices can be manufactured to reduce the amount of aggregating metals that may release into the stored solutions or the device can be cleaned with acid and basic washes. Examples of other storage devices include ampoules (40, Fig. 4), vials (45, Fig 4) and bags (50, Fig. 4).
[0035] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
EXAMPLES
Example 1 - General Procedure for Determination of Aggregating Metal Release: [0036] The following procedure can be used to determine the amount of aggregating metals released into a solution after storage.
[0037] A random selection of containers in which Interferont is to be stored is selected from a manufacturing lot. Each container in the random selection is filled with a placebo formulation including all of the components of the formulation except lnterferon-ß. The filled containers are stored at ambient temperature for a period of about greater than 360 minutes. The placebo formulations are analyzed by any suitable means to determine the concentration of aggregating metals. Suitable analytical methods include, but are not limited to, Inductively Coupled Mass Spectrometry and Atomic Absorption Spectroscopy.
Example 2- Determination of Aggregating Metal Release from Avon ex®: [0038] Avonex® liquid formulation contains Interferon-ß-1a, sodium acetate trihydrate, glacial acetic acid, arginine hydrochloride and polysorbate-20 in Water For Injection (WFI). Specifically, each 0.5 mL (30 meg dose) of Avonex® in a prefilled glass syringe contains 30 meg of lnterferon-ß-1a, 0.79 mg sodium acetate trihydrate, 0.25 mg glacial acetic acid, 15.8 mg arginine hydrochlo- ride and 0.025 mg polysorbate-20 in WFI at a pH of approximately 4.8. The placebo formulation is prepared by combining each of the components of the Avonex® formulation minus the lnterferon-ß-1a. Examples of formulations of lnterferon-ß are described in International Publication No. WO 98/28007 the entire contents of which are incorporated herein by reference. A random sample of syringes, such as 60, from a manufacturing lot is selected to evaluate the amount of aggregating metals released into stored solutions. The syringes are filled with the placebo formulation and stored for a period of between 360 to 480 minutes, optionally with sonication for about 5 minutes at room temperature. A sample of the placebo formulation is analyzed by Inductively Coupled Mass Spectrometry to determine the amount of aggregating metals.
Claims 1. A method for producing a device that includes a housing for retaining a solution of lnterferon-ß, wherein the method comprises: (a) cleaning the housing with acid and basic washes so as to remove or reduce the amount of aggregating metal on the surface that, in use, would be in direct contact with the solution of lnterferon-ß; (b) filling the solution of lnterferon-ß into the housing, wherein, after filling the solution, the housing releases a concentration of aggregating metal into the solution of less than 500 parts per billion afterthe solution is retained in the housing for greater than about 10 minutes. 2. A method for producing a device that includes a housing for retaining a solution of lnterferon-ß, wherein the method comprises: (a) constructing the housing so as to reduce the amount of aggregating metal on the surface that, in use, would be in direct contact with the solution of lnterferons-ß; (b) filling the solution of lnterferon-ß into the housing, wherein, after filling the solution, the housing releases a concentration of aggregating metal into the solution of less than 500 parts per billion afterthe solution is retained in the housing for greater than about 10 minutes. 3. The method of Claim 1 or Claim 2, wherein the housing releases a concentration of aggregating metal of less than about 500 parts per billion afterthe solution is retained in the housing for greater than about 120 minutes. 4. The method of Claim 1 or Claim 2, wherein the hous ing releases a concentration of aggregating metal of less than about 500 parts per billion afterthe solution is retained in the housing for greater than about 360 minutes. 5. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 500 parts per billion afterthe solution is retained in the housing for greater than about 480 minutes. 6. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 500 parts per billion afterthe solution is retained in the housing for about 120 minutes to about 480 minutes. 7. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 500 parts per billion afterthe solution is retained in the housing for about 300 minutes to about 420 minutes. 8. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 250 parts per billion. 9. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 100 parts per billion. 10. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 75 parts per billion. 11. The method of Claim 1 orClaim 2, wherein the housing releases a concentration of aggregating metal of less than about 50 parts per billion. 12. The method of Claim 1 or Claim 2, wherein aggregation of lnterferon-ß caused by aggregating metal in the solution is less than 15% after storage. 13. The method of Claim 1 or Claim 2, wherein aggregation of lnterferon-ß caused by aggregating metal in the solution is less than 10% after storage. 14. The method of Claim 1 or Claim 2, wherein aggregation of lnterferon-ß caused by aggregating metal in the solution is less than 5% after storage. 15. The method Claim 1 orClaim 2, wherein aggregation of lnterferon-ß caused by aggregating metal in the solution is less than 2% after storage. 16. A device comprising: (a) a housing for retaining a solution of Interfer- on-ß; (b) a solution of lnterferon-β retained within the housing, wherein the housing releases a concentration of aggregating metal into the lnterferon-β solution of less than 500 parts per billion after the solution is retained in the housing for greater than about 10 minutes. 17. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 250 parts per billion. 18. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 100 parts per billion. 19. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 75 parts per billion. 20. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 50 parts per billion. 21. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 500 parts per billion after the solution is retained in the housing for greater than about 120 minutes. 22. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 500 parts per billion after the solution is retained in the housing for greater than about 360 minutes. 23. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 500 parts per billion after the solution is retained in the housing for greater than about 480 minutes. 24. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 500 parts per billion after the solution is retained in the housing for about 120 minutes to about 480 minutes. 25. The device of Claim 16, wherein the housing releases a total concentration of aggregating metal of less than about 500 parts per billion after the solution is retained in the housing for about 300 minutes to about 420 minutes. 26. The device of Claim 16, wherein the aggregation of Interferon-ß caused by aggregating metal in the solution is less than 15% after storage. 27. The device of Claim 16, wherein the aggregation of Interferon-ß caused by aggregating metal in the solution is less than 10% after storage. 28. The device of Claim 16, wherein the aggregation of Interferon-ß caused by aggregating metal in the solution is less than 5% after storage. 29. The device of Claim 16, wherein the aggregation of Interferon-ß caused by aggregating metal in the solution is less than 2% after storage. 30. The method of any one of Claims 1-15, or the device of any one of Claims 16-29, wherein the aggregating metal is selected from the group comprising iron, copper, nickel, molybdenum and tungsten. 31. The method or device of Claim 30, wherein the aggregating metal is tungsten. 32. The method of any one of Claims 1-15, or the device of any one of Claims 16-29, wherein the device is a syringe, bottle, vial or a bag. 33. The method or device of Claim 32, wherein the device is a syringe. 34. The method of any one of Claims 1-15, or the device of any one of Claims 16-29, wherein the housing of the device is constructed of glass, metal or plastic. 35. The method of Claim 34, wherein the housing is constructed of glass. 36. The method of any one of Claims 1-15 or 30-35, or the device of any one of Claims 15-35, wherein the Interferon-ß is lnterferon-ß-1a.
Patentansprüche 1. Verfahren zum Produzieren einer Vorrichtung, welche ein Gehäuse zum Aufbewahren einer Interferon-ß-Lösung enthält, wobei das Verfahren umfasst: a) Reinigen des Gehäuses mit sauren und basischen Spülungen, sodass die Menge an aggregierendem Metall auf der Oberfläche, die bei Verwendung in direktem Kontakt mit der Inter-feron-ß-Lösung wäre, entfernt oder reduziert wird; b) Einfüllen der Interferon-ß-Lösung in das Gehäuse, wobei das Gehäuse nach dem Einfüllen der Lösung eine Konzentration von aggregierendem Metall von unter 500 parts per billion in die Lösung abgibt, nachdem die Lösung für über etwa 10 Minuten in dem Gehäuse aufbewahrt ist. 2. Verfahren zum Produzieren einer Vorrichtung, welche ein Gehäuse zum Aufbewahren einer Interferon-ß-Lösung enthält, wobei das Verfahren umfasst: a) Konstruieren des Gehäuses, sodass die Menge an aggregierendem Metall auf der Oberfläche, die bei Verwendung in direktem Kontakt mit der Interferon-ß-Lösung wäre, reduziert wird; b) Einfüllen der Interferon-ß-Lösung in das Gehäuse, wobei das Gehäuse nach dem Einfüllen der Lösung eine Konzentration von aggregierendem Metall von unter 500 parts per billion in die Lösung abgibt, nachdem die Lösung für über etwa 10 Minuten in dem Gehäuse aufbewahrt ist. 3. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 120 Minuten in dem Gehäuse aufbewahrt ist. 4. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 360 Minuten in dem Gehäuse aufbewahrt ist. 5. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 480 Minuten in dem Gehäuse aufbewahrt ist. 6. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für etwa 120 Minuten bis etwa 480 Minuten in dem Gehäuse aufbewahrt ist. 7. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für etwa 300 Minuten bis etwa 420 Minuten in dem Gehäuse aufbewahrt ist. 8. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 250 parts per billion abgibt. 9. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 100 parts per billion abgibt. 10. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregieren dem Metall von unter etwa 75 parts per billion abgibt. 11. Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter etwa 50 parts per billion abgibt. 12. Verfahren nach Anspruch 1 oder Anspruch 2, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 15 % beträgt. 13. Verfahren nach Anspruch 1 oder Anspruch 2, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 10 % beträgt. 14. Verfahren nach Anspruch 1 oder Anspruch 2, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 5 % beträgt. 15. Verfahren nach Anspruch 1 oder Anspruch 2, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 2 % beträgt. 16. Vorrichtung, umfassend: a) ein Gehäuse zum Aufbewahren einer Interferon-ß-Lösung; b) eine in dem Gehäuse aufbewahrte Interferon-ß-Lösung, wobei das Gehäuse eine Konzentration von aggregierendem Metall von unter 500 parts per billion in die Interferon-ß-Lösung abgibt, nachdem die Lösung für über etwa 10 Minuten in dem Gehäuse aufbewahrt ist. 17. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 250 parts per billion abgibt. 18. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 100 parts per billion abgibt. 19. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 75 parts per billion abgibt. 20. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 50 parts per billion abgibt. 21. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 120 Minuten in dem Gehäuse aufbewahrt ist. 22. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 360 Minuten in dem Gehäuse aufbewahrt ist. 23. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für über etwa 480 Minuten in dem Gehäuse aufbewahrt ist. 24. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für etwa 120 Minuten bis etwa 480 Minuten in dem Gehäuse aufbewahrt ist. 25. Vorrichtung nach Anspruch 16, wobei das Gehäuse eine Gesamtkonzentration von aggregierendem Metall von unter etwa 500 parts per billion abgibt, nachdem die Lösung für etwa 300 Minuten bis etwa 420 Minuten in dem Gehäuse aufbewahrt ist. 26. Vorrichtung nach Anspruch 16, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 15 % beträgt. 27. Vorrichtung nach Anspruch 16, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 10 % beträgt. 28. Vorrichtung nach Anspruch 16, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 5 % beträgt. 29. Vorrichtung nach Anspruch 16, wobei die Aggregation von lnterferon-ß, welche durch das aggregierende Metall in der Lösung verursacht wurde, nach Lagerung unter 2 % beträgt. 30. Verfahren nach einem der Ansprüche 1-15oderVor-richtung nach einem der Ansprüche 16-29, wobei das aggregierende Metall aus der aus Eisen, Kupfer, Nickel, Molybdän oder Wolfram bestehenden Gruppe ausgewählt ist. 31. Verfahren oder Vorrichtung nach Anspruch 30, wobei das aggregierende Metall Wolfram ist. 32. Verfahren nach einem der Ansprüche 1-15 oder Vorrichtung nach einem der Ansprüche 16-29, wobei die Vorrichtung eine Spritze, Flasche, Ampulle oder ein Beutel ist. 33. Verfahren oder Vorrichtung nach Anspruch 32, wobei die Vorrichtung eine Spritze ist. 34. Verfahren nach einem der Ansprüche 1-15 oderVor-richtung nach einem der Ansprüche 16-29, wobei das Gehäuse der Vorrichtung aus Glas, Metall oder Kunststoff gestaltet ist. 35. Verfahren nach Anspruch 34, wobei das Gehäuse aus Glas gestaltet ist. 36. Verfahren nach einem der Ansprüche 1-15 oder 30-35 oder Vorrichtung nach einem der Ansprüche 15-35, wobei das lnterferon-ß lnterferon-ß-1a ist.
Revendications 1. Procédé de fabrication d’un dispositif qui comprend un boîtier destiné â retenir une solution d’interféron ß, dans lequel le procédé comprend : (a) le nettoyage du boítier avec des solutions acides et basiques de maniêre â éliminer ou ré-duire la quantité d’agrégation de métái sur la surface qui, en utilisation, seraiten contactdirect avec la solution d’interféron ß ; (b) le remplissage de la solution d’interféron ß dans le boítier, dans lequel, aprês le remplissage de la solution, le boítier libére une concentration d’agrégation de métái dans la solution de moins de 500 parties par milliard aprés que la solution est retenue dans le boítier pendant plus d’environ 10 minutes. 2. Procédé de fabrication d’un dispositif qui comprend un boítier destiné â retenir une solution d’interféron ß, dans lequel le procédé comprend : (a) la construction du boítier de maniêre â ré-duire la quantité d’agrégation de métái sur la surface qui, en utilisation, seraiten contactdirect avec la solution d’interféron ß ; (b) le remplissage de la solution d’interféron ß dans le boítier, dans lequel, aprés remplissage de la solution, le boítier libére une concentration d’agrégation de métái dans la solution de moins de 500 parties par milliard aprés que la solution est retenue dans le boítier pendant plus d’environ 10 minutes. 3. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boítier libére une concentration d’agrégation de métái inférieure â environ 500 parties par milliard aprés que la solution est retenue dans le boîtier pendant plus d’environ 120 minutes. 4. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 500 parties par milliard aprés que la solution est retenue dans le boîtier pendant plus d’environ 360 minutes. 5. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 500 parties par milliard aprês que la solution est retenue dans le boîtier pendant plus d’environ 480 minutes. 6. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 500 parties par milliard aprês que la solution est retenue dans le boTtier pendant environ 120 minutes â environ 480 minutes. 7. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 500 parties par milliard aprês que la solution est retenue dans le boTtier pendant environ 300 minutes â environ 420 minutes. 8. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 250 parties par milliard. 9. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boîtier libêre une concentration d’agrégation de métái inférieure â environ 100 parties par milliard. 10. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boTtier libêre une concentration d’agrégation de métái inférieure â environ 75 parties par milliard. 11. Procédé selon la revendication 1 ou la revendication 2, dans lequel le boTtier libêre une concentration d’agrégation de métái inférieure â environ 50 parties par milliard. 12. Procédé selon la revendication 1 ou la revendication 2, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 15 % aprës stockage. 13. Procédé selon la revendication 1 ou la revendication 2, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 10 % aprés stockage. 14. Procédé selon la revendication 1 ou la revendication 2, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 5 % aprés stockage. 15. Procédé selon la revendication 1 ou de la revendication 2, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 2 % aprés stockage. 16. Dispositif comprenant: (a) un boîtier destiné â retenir une solution d’interféron ß ; (b) une solution d’interféron ß retenue â l’inté-rieur du boTtier, dans lequel le boîtier libêre une concentration d’agrégation de métái dans la solution d’interféron ß de moins de 500 parties par milliard aprés que la solution est retenue dans le boTtier pendant plus de 10 minutes environ. 17. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 250 parties par milliard. 18. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 100 parties par milliard. 19. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 75 parties par milliard. 20. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 50 parties par milliard. 21. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 500 parties par milliard aprés que la solution est retenue dans le boTtier pendant plus de 120 minutes environ. 22. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 500 parties par milliard aprés que la solution est retenue dans le boTtier pendant plus de 360 minutes environ. 23. Dispositif selon la revendication 16, dans lequel le boTtier libére une concentration totale d’agrégation de métái inférieure â environ 500 parties par milliard aprés que la solution est retenue dans le boTtier pendant plus de 480 minutes environ. 24. Dispositif selon la revendication 16, dans lequel le boîtier libêre une concentration totale d’agrégation de métái inférieure â environ 500 parties par milliard aprês que la solution est retenue dans le boîtier pendant environ 120 minutes â environ 480 minutes. 25. Dispositif selon la revendication 16, dans lequel le boîtier libêre une concentration totale d’agrégation de métái inférieure â environ 500 parties par milliard aprês que la solution est retenue dans le boîtier pendant environ 300 minutes â environ 420 minutes. 26. Dispositif selon la revendication 16, dans lequel l’agrégation d’interféron ß provoquée par l’agréga-tion de métái dans la solution est inférieure â 15 % aprês stockage. 27. Dispositif selon la revendication 16, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 10 % aprés stockage. 28. Dispositif selon la revendication 16, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 5 % aprés stockage. 29. Dispositif selon la revendication 16, dans lequel l’agrégation d’interféron ß provoquée par l’agrégation de métái dans la solution est inférieure â 2 % aprés stockage. 30. Procédé selon l’une quelconque des revendications 1 â 15, ou dispositif selon l’une quelconque des revendications 16 â 29, dans lequel l’agrégation de métái est choisie dans le groupe comprenant le fér, le cuivre, le nickel, le molybdéne et le tungsténe. 31. Procédé ou dispositif selon la revendication 30, dans lequel l’agrégation de métái est du tungsténe. 32. Procédé selon l’une quelconque des revendications 1 â 15, ou dispositif selon l’une quelconque des revendications 16 a 29, dans lequel le dispositif est une seringue, une bouteille, un flacon ou une poche. 33. Procédé ou dispositif selon la revendication 32, dans lequel le dispositif est une seringue. 34. Procédé selon l’une quelconque des revendications 1 â 15, ou dispositif selon l’une quelconque des revendications 16 â 29, dans lequel le boítier du dispositif est construit en vérré, en métái ou en plasti-que. 35. Procédé selon la revendication 34, dans lequel le boítier est construit en vérré. 36. Procédé selon l’une quelconque des revendications 1 â 15 ou 30 â 35, ou dispositif selon l’une quelconque des revendications 15 â 35, dans lequel l’inter-féron ß est de l’interféron ß-1a.

Claims (13)

MôÄSlil ï,' EgyiiS^älÄl^lészltésêii^l^tô módszer, amely ioiéf#rön-jj| oldat tárolására mlû burkolatot tartalma?, ahol a móstar» következőket fpgláíja magéba«; .;{&amp;) a; burkolat tisztftásá savas és hlzíSös mosással m aigregáfó lét« el távolítása hős mennyiségének csökkeméséheí azon a felületen, amely használat során közvetlenül érintkezne az intetfertih'-ßöibattali (b) az interferon^ oldat betöltése a hufiöláiha, ahol at oldat betöltése után a burkolat adott :koneentráésO|b aggregáió fémet bocsát kf a? oldatba kevesebb, mint SQö ppb mennyiségben, miután az oldat körülbelül 10 percnél hosszabb ideig marad a burkolatban.MôÄSlil ï, 'Unique method of preparation, which is a method of preparation. a solution for storing a solution with a myriad of wrappers? .; {&amp;)a; To clean the casing with acidic and heat-resistant washings, remove the amount of hero on the surface that would be in direct contact with the loading of the interferon-α solution in the intetfertih-ßöbattali (b), where the envelope is loaded after the solution of solution: b gives aggregation metal kf a? in less than about 10 ppb of solution after the solution remains in the casing for more than about 10 minutes. 2. Egy olyan eszköz készítésére szolgáló módszer, amely interferon-^ oldat tárolására való burkolatot tartalma?,, ahol a módszer * követkézét (aj á burkbiat élkésäMse olyan modonj bogy csökkenjen az agiréiáli lém mennyisége azon a féiületeoy amely hássríálat soráitközvetlenüi érintkezne az interferon^ oldattál; (b)az interferon·# oldat betöltése a burkolatba... ahol a:? óidat betöltése után a burkolat adott koncentrációjú aggregéit) lémet bocsát ki m. öídaiha kevesebb, mint 50Θ ppb mennyiséiben, mmtán az olnat körülbelül 10 pmcne! hosszabb ideig mo»ad a burkolatban.2. A method for preparing a device for storing interferon-solution solution, wherein the method is followed by a reduction in the amount of agaric fluid in the semiconductor line of direct contact with the interferon solution. (b) loading the solution of interferon # # into the casing ... where:? it is less than 50Θ ppb in quantity, but it is about 10 pmcne! longer in the case. 3, Az 1, vagy 2. igénypont szerinti módszer., ahol a burkolat adott koncentrációjú aggregük) fémet bocsát ki kevesebb, mint SÖÖ ppb mennyiségben, miután a? oldat 220 pércnál hösszabb ideig marad a burkolatban, 4 Az %. mw%> I^WpM^Hntl: :tói»p:ihdfe:a liÉi adott koncentrációjú aggregáló fémet bocsát kÜ ppb mennyiségben, miután át oldat 360 percnél hosszabb ideig marad sburkoiatbaaThe method of claim 1 or claim 2, wherein the casing is of a given concentration aggregate) emitting less than? solution remains in the case for more than 220 lbs, 4%. mw% <RTI ID = 0.0> ll-WpM ^ Hntl: </RTI> p: ihdfe: the liIi emits aggregate metal with a given concentration in ppb after the solution remains in the solution for more than 360 minutes 5. Az 1. vagy 2. igénypont szerinti módszer, ahol a burkolat adott koncentrációjú aggregáió fémet bocsát ki kevesebb, mint 500 ppb mennvnégben. miután az oldat 480 percnél hosszabb ideig marad a burkolatban.The method according to claim 1 or 2, wherein the casing emits aggregate metal of a given concentration at less than 500 ppb. after the solution remains in the casing for more than 480 minutes. 8, Az i, vagy 2, Igénypont szerinti módszer, aboi: a burkolat adott koncentrációjú aggregéin: fémet bocsát ki kevesebb, mint SuO ppb mennyiségben, miután az oldat körülbeíül 120~480:perelg marad a burkolatban.8, The method of claim i, or 2, aboi: on a given concentration of aggregate of the casing: emits less than SuO ppb of metal after the solution is about 120 ~ 480: remains in the casing. 7. Az l. vagy 2. Igénypont szerinti módszer, ahol: a burkolat adoft.ikébcemrádé|é ffrdet bocsát ki kevesebb, mint SOÖ ppb mennyiségben, miután az oldat körülbelül 3Í50-42O percig marad a burkolatban. S, Az 1, vagy 2. igénypont szerinti: módszer, ahol a burkolat adott köncetfrrációju sggregié lémet bocsát k;i kevesebb, mint 2S£); ppb mennyiségben.7. The l. or 2. The method of claim, wherein: the envelope emits less than about SO3 ppb after the solution remains in the casing for about 35050-42o minutes. A method according to claim 1 or claim 2, wherein the casing produces a sggregate of less than 2S of lint; ppb. 3. Az 1. vagy 2, igénypont szerinti módszer, ahoi a burkolat adott koncentrációjú aggregáló fémet bocsát ki kevesebb, mint ,100 ppb mennyiségben. M*. Az I. vagy I. igénypont szerinti módszer, aböl â burkolat adott köneontfácidjú aggregáló fémet bocsát ki kevesebb, mint 75 ppb mennyiségben.The method according to claim 1 or 2, wherein the casing emits a concentration of aggregate metal of less than 100 ppb. M *. The method of claim I or I, wherein the casing emits a given rope-phase-aggregating metal in an amount of less than 75 ppb. 11. Az 1. vagy 2. igénypont szerinti módszer, ahoi a burkolat adott feobpentrációjú aggregáló fémet bocsát ki kevesebb, mint 50 ppb mennyiségben.The method according to claim 1 or 2, wherein the casing emits an aggregate metal having a concentration of less than 50 ppb. 12, Az 1, vagy 2. Igénypont szerinti módszer, ahol az oldatban az aggregéiő fém által okozott interferonzp aggfégáiódásá kevesebb; mint 1¾ tárolás után, .13. Az 1. vagy 2. igénypont szerinti módszer, ahoi az oldatban az aggregáló lm által okozott interferon-p aggregálódása kevesebb, punt Iö% tároiás után.The method of claim 1 or 2, wherein the interferonzp caused by aggregate metal in the solution is less potent; than after 1¾ storage, .13. The method of claim 1 or 2, wherein the aggregation of the interferon-β caused by aggregating β in the solution is less, after p.i.%% retention. 14. Az i, vagy 2, igliypóót: tgifUtf ahol az oldatban az aggregálö fém által okozott interferon-p aggregálódása kevesebb, mini 5% tároiás után. 1.5 Az 1. vagy 2. igénypont szerinti módszer, ahol az oldatban az aggregáló fém által okozott mieríéron-B aggregálódása kevesebb, mint 2% tároiás után.14. I, or 2, igliypóto: tgifUtf where the aggregation of the interferon-p caused by aggregating metal in the solution is less, min 5% after storage. 1.5 The method of claim 1 or 2, wherein the aggregate metal-mediated aggregate-B aggregation in the solution is less than 2% after storage. 16. Egy eszköz, amely a következőket tartalmazza: (aj egy inierferon-g o:dat tárolására vaíó burkolat; (fej a burkolatban zárolt interferon-ß oldat, abc; a burkolat adott koncentrációjú aggregéi fémet bocsát ki az interferon-p: óidatba ikevesebb, mint: :$öö ppb mennyiségben, irrilbtán az oldat kbrüibeiul :M percnél hosszabb ideig márad: a: burkolatban. 1.7. A: 16, igénypont szerinti módszer, ahol a burkdiát adott ósszkoncentrációíú aggregáló fémet bocsát ki kevesebb, mint 250 ppb mennyiségben, 18. A 16, igénypont szerinti módszer, ahol a burkolat adott ósszkoncentrációjó aggregáló: fémet bocsát ki kevesebb, mint 100 ppo mennyiségben. .lit: >A 16. igénypont szerinti módszer, ahol a burkolat adott összkoncenírádóju éggregáló fémet bocsát ki kevesebb, mint 75 ppb ^mennyiségben, 20. A 16, igénypont szerinti mobstery ahol a burkolat adott összkoncentráctóiú aggregáló fémet bocsát ki kevesebb, mint 50 ppb mennyiségben.. 21. A 16. igénypont, szerinti módszer, ahoi a burkolat adott összkoncemrációjú aggregáló fémet bocsát ki kevesebb, mint §00 ppb mennyiségben, miután az oldat 12Öperenéí hesszahh ideig marad a burkolatban. 2¾. A 16, igénypont Metioti mMzer, ahoi δ Öútkoiat ä d ött iS szakis n cé nt rác IÖ j iu aggregáió féméi bocsát ki kevesebb, mint SÖÖ ppb; mennyiségben, mintán áz oldat 360 pMcnéí hosszabb ideig marad a burkolatban.16. A device comprising: (a cover for storing an inierferon-g o: data; (head-interferon-ß-solution blocked in the casing; abc; aggregates of a given concentration of the casing emit metal less than interferon-β). such as:: $ night in ppb, irrespective of the solution, the solution is brewed for more than a minute: a: in the casing 1.7 A method according to claim 16, wherein the envelope emits an aggregate metal of less than 250 ppb at a given concentration of agglutination, The method of claim 16, wherein the casing has a particular high concentration of aggregation: emits less than 100 ppo.> The method of claim 16, wherein the casing emits a total aggregate of less than 75 aggregate metal. ppb ^ in amount 20. The mobstery of claim 16, wherein the casing emits aggregate metal having a total concentration of less than 50 ppb. The method of claim 16, wherein the casing emits an aggregate metal of less than 0000 ppb with a given total concrement after the solution remains in the casing for 12 hours. 2¾. Metioti mMzer of claim 16, wherein the metals of the aggregation of the δ pathway are less than PÖB ppb; 360 pMcn of the sample gas solution remains in the casing for a longer time. 21. A li> igénypont szerinti módszer, afcöî a burkolat adott ëïMonbéttfâei^i: .agitáló. lÉiëî' bocsát ki kevesebb, mint 5QO ppb mennyiségben, miután 3?. óidét 480 peronéi hosszabb ideig marad a burkoltban. 24. A 16. igénypont szerint; módszer, ahoi a burkolat adott összkoncsntraeícjű aggregéin fémet bocsát ki kevesebb, mint 500 ppb mennyiségben, miután az oldat körülbelül 120-480 percig marad e burkolatban. 25. A 16. igénypont szerinti módszer,, ahol a burkolat, adott összkoneentrációjú aggregálo fémet becsét ki kevesebb, mint 500 ppb mennyiségben, miután az oldat körülbelül 500-42.0 percig marad a burkolatban.21. The method of claim 1, wherein said coating is a agitator. lÉiëî 'emits less than 5QO ppb after 3 ?. 480 platforms will remain in the enclosure for longer. 24. The method of claim 16; a method wherein the casing emits a metal of less than 500 ppb on a given aggregate aggregate after the solution remains in the casing for about 120 to 480 minutes. The method of claim 16, wherein the casing shuts off aggregate metal having a total concentration of less than 500 ppb after the solution remains in the casing for about 500 to 42.0 minutes. 26. Az 1», igénypont szerinti módszer, abol az aggregaii Mrd Utal okozott sntsrferöO'-ß sggregáióríása kevesebb, mint 15% tároiás után. 2?, Az Ä igénypont szerint) módszer, ahol m. aggrégátó fém áltál okozott lóterferen^ aggregálódáisa kevesebb, mint 10% tárolás után, Ä Az 26. igénypont szerinti módszer, ahol M sggfégáfó fém által okozott Interferomß 4g$tégálödása kevesebb, mint. 5% tárolás után,26. The method of claim 1, wherein the aggregation of a sntsrfero-ß caused by the aggregate Mrd is less than 15% after storage. 2?, According to claim Ä), where m. Aggregate-metal-induced horse interferences after less than 10% of storage, Δ The method of claim 26, wherein the Interferomß 4g of gold is caused by a melting metal of less than. 5% after storage 29. Az 16 igénypont szerinti módszer, ahoi az aggregáió fém áits! okozott interferon-ß aggregálotíása kevesebb, mint 2% tároiás u fán.29. The method of claim 16, wherein the aggregation is metal. aggregation of interferon-ß induced by less than 2% on storing u tree. 30. Az 1·"Ί5, igénypontok bármelyike szerinti módszer vagy 3 16-29, Igénypontok bármelyike szerinti eszköz, ahol az aggregáió fémet a következőket tartalmazó csoportból választják ki: vas, réz, nikkel, moiibdén és voiírárn. 31. A 30.: igénypont szerinti módszer vagy eszköz, ebei azaggregllö fém voífrám. 32:, Az i-15:, igénypontöki'iárrnéiyíke szerint!:módszer vagy 3 36-29. igénypontok bármelyike szerinti eszköz, ébói fiola vágy tássfc, 33. A 32. igénypont szerinti módszer vagy eszköz, ahol az eszköz fecskendő. 34:. Az 1-19, igénypontok bármelyike szerinti módszer vagy a: 16-29, igénypontok bármelyike szerinti eszköz, a hol az eszköz a nyage üveg, fém vagy mils nyag. IS, A SA. igénypont szerinti módszer, ahol a burkotatevegböi keszüit. W. ki 1--1S, ês 38-35, igénypontok bármelyike szerinti módszer vagy 3 1§·~3Ι. igënypeniOK bármelyike szerinti eszköz, ahol az snterferon'fi interferan-fH 3.The method according to any one of claims 1 to 4, or a device according to any one of claims 16 to 29, wherein the aggregation metal is selected from the group consisting of iron, copper, nickel, moibybdenum, and sulfur. The method or device according to claim 1, wherein the method according to any one of claims 32 to 29 is a method according to any one of claims 32 to 29, wherein the method according to any one of claims 1 to 15 is a method. method or device wherein the device is a syringe 34: A method according to any one of claims 1 to 19 or a device according to any one of claims 16 to 29, wherein the device is a glass, metal or mastic. The method according to claim 1, wherein the method of claim 1 is a method according to any one of claims 1-1, or 38-35, or a device according to any one of claims 1 to 3, wherein said snterferon is interferan-fH 3.
HUE06718129A 2005-01-12 2006-01-11 Method for delivering interferon-beta HUE031061T2 (en)

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